Previous studies of mice infected with LP-BM5 murine leukemia viruses showed that they exhibit many immunologic abnormalities described for AIDS patients infected with human immunodeficiency viruses. The current studies were developed to determine the pathogenesis of these defects in mice. In parallel with studies of man, it was found that cytotoxic T lymphocyte responses to "self plus x" antigens are lost before reactivity to allo-antigens. Studies of terminal mice showed that they died with B cell lymphomas with frequent brain involvement. Development of lymphomas was shown to progresss from polyclonal B cell stimulation through oligoclonal proliferation to terminal neoplasia. Enhanced susceptibility to infection consequent to immunosuppression was shown by the fact that C57BL/6 mice, normally resistant to ectromelia virus, die with ectromelia if previously exposed to Lp-BM5 viruses. Analyses of lymphokine production by cells of infected mice showed deficiencies in expression of IL-2, alpha, beta and gamma interferon. By comparison, expression of BSF-1 appears to be normal or perhaps increased. Finally mice infected with LP-MB5 MuLV show decreased NK activity. However, NK or LAK activity and CTL responses can be restored by providing exogenous IL-2. These results suggest that studies of mice infected with LP-BM5 viruses may provide important insights into the mechanisms of immunosuppression induced by retroviruses.